The overall objectives of this program are to develop a detailed understanding of the molecular and structural basis for the genesis and assembly of the red cell, with emphasis on the membrane skeleton; and to develop an improved mechanistic understanding of erythropoiesis, with the goal of defining pathophysiologic mechanisms of anemia, a major health problem affecting over billion individuals around the world. The scope of the proposed research program also includes delineating the role of cytoskeleton in regulating hematopoietic cell differentiation. To achieve these broad goals, four complementary approaches are proposed: 1) Develop a detailed understanding of the molecular and structural basis for the functions of an important family of cytoskeletal proteins in erythroid cells; 2) Obtain detailed mechanistic understanding of the functional and biological consequences of interaction between proteins of the malarial parasite and the red cell; 3) Delineate mechanisms involved in enucleation and membrane biogenesis during terminal erythroid differentiation; and 4) Obtain mechanistic understanding of the role of the bone marrow matrix stiffness on hematopoiesis, with particular emphasis on erythropoiesis. To achieve these objectives, a group of investigators with expertise in hematology, biochemistry, cell biology, biophysics, genetics, parasitology, and molecular biology, as well as a long standing interest in red cell membrane physiology, have come together to mount a concerted effort. It is anticipated that information garnered during these studies will contribute towards increased insights into the role of skeletal proteins in membrane assembly, homeostasis and structure-function relationships in erythroid cells in particular, and somatic cells in general, that will have significant impact on our understanding of the pathophysiology of important human diseases.